Genetic Variant SIRT3:p.Pro262His (chr11-230474-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012239.6(SIRT3):c.785C>A(p.Pro262His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,505,370 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 40 hom. )

Consequence

SIRT3
NM_012239.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.70

Variant links:

Genes affected

SIRT3 (HGNC:14931): (sirtuin 3) SIRT3 encodes a member of the sirtuin family of class III histone deacetylases, homologs to the yeast Sir2 protein. The encoded protein is found exclusively in mitochondria, where it can eliminate reactive oxygen species, inhibit apoptosis, and prevent the formation of cancer cells. SIRT3 has far-reaching effects on nuclear gene expression, cancer, cardiovascular disease, neuroprotection, aging, and metabolic control. [provided by RefSeq, May 2019]

SIRT3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055104196).

BP6

Variant 11-230474-G-T is Benign according to our data. Variant chr11-230474-G-T is described in ClinVar as [Benign]. Clinvar id is 782538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00984 (1499/152262) while in subpopulation AFR AF= 0.023 (956/41546). AF 95% confidence interval is 0.0218. There are 13 homozygotes in gnomad4. There are 698 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT3	NM_012239.6 link	c.785C>A	p.Pro262His	missense_variant	Exon 4 of 7	ENST00000382743.9	NP_036371.1	Q9NTG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT3	ENST00000382743.9 link	c.785C>A	p.Pro262His	missense_variant	Exon 4 of 7	1	NM_012239.6	ENSP00000372191.4		Q9NTG7-1

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

1494

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00545

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.00519

AC:

976

AN:

187926

Hom.:

AF XY:

0.00469

AC XY:

483

AN XY:

103086

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.00738

Gnomad ASJ exome

AF:

0.00118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00174

Gnomad FIN exome

AF:

0.0000979

Gnomad NFE exome

AF:

0.00522

Gnomad OTH exome

AF:

0.00754

GnomAD4 exome

AF:

0.00550

AC:

7445

AN:

1353108

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3651

AN XY:

669682

show subpopulations

Gnomad4 AFR exome

AF:

0.0205

Gnomad4 AMR exome

AF:

0.00813

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00193

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00563

Gnomad4 OTH exome

AF:

0.00706

GnomAD4 genome

AF:

0.00984

AC:

1499

AN:

152262

Hom.:

Cov.:

AF XY:

0.00938

AC XY:

698

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0230

Gnomad4 AMR

AF:

0.00824

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00621

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00576

AC:

699

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.84

T;T;T;D;T

MetaRNN

Benign

0.0055

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;N;N;D;N

REVEL

Benign

0.16

Sift

Uncertain

0.022

D;T;D;D;T

Sift4G

Benign

0.064

T;T;T;D;T

Polyphen

0.98

D;P;D;D;.

Vest4

0.21

MVP

0.50

MPC

0.30

ClinPred

0.030

GERP RS

2.1

Varity_R

0.18

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over